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Deafness and Loss of Cochlear Hair Cells in the Absence Of www.nature.com/scientificreports OPEN Deafness and loss of cochlear hair cells in the absence of thyroid hormone transporters Slc16a2 Received: 20 July 2017 Accepted: 16 February 2018 (Mct8) and Slc16a10 (Mct10) Published: xx xx xxxx David S. Sharlin1,2, Lily Ng2, François Verrey 3, Theo J. Visser4, Ye Liu2, Rafal T. Olszewski5, Michael Hoa5, Heike Heuer6 & Douglas Forrest2 Transmembrane proteins that mediate the cellular uptake or efux of thyroid hormone potentially provide a key level of control over neurodevelopment. In humans, defects in one such protein, solute carrier SLC16A2 (MCT8) are associated with psychomotor retardation. Other proteins that transport the active form of thyroid hormone triiodothyronine (T3) or its precursor thyroxine (T4) have been identifed in vitro but the wider signifcance of such transporters in vivo is unclear. The development of the auditory system requires thyroid hormone and the cochlea is a primary target tissue. We have proposed that the compartmental anatomy of the cochlea would necessitate transport mechanisms to convey blood-borne hormone to target tissues. We report hearing loss in mice with mutations in Slc16a2 and a related gene Slc16a10 (Mct10, Tat1). Defciency of both transporters results in retarded development of the sensory epithelium similar to impairment caused by hypothyroidism, compounded with a progressive degeneration of cochlear hair cells and loss of endocochlear potential. Administration of T3 largely restores the development of the sensory epithelium and limited auditory function, indicating the T3-sensitivity of defects in the sensory epithelium. The results indicate a necessity for thyroid hormone transporters in cochlear development and function. Neurodevelopment is known to require adequate thyroid hormone in the circulation but for many years, little attention was given to questions of access of the hormone to target tissues1,2. Te necessity for proteins that trans- port hormone across the plasma membrane of cells was indicated by fnding mutations in solute carrier SLC16A2 (monocarboxylate transporter 8, MCT8) in Allan-Herndon-Dudley syndrome, an X-linked disorder of psych- omotor and speech retardation3,4. SLC16A2 has 12 transmembrane domains and transports the active form of thyroid hormone, T3, and its precursor T45. In vitro studies have identifed other proteins that transport T3 or T4 among other substrates, suggesting that the current picture of thyroid hormone transport is far from complete6. Moreover, it has been suggested that Slc16a2 cooperates with organic anion transporter Oatp1c1 (Slco1c1)7 or L-type amino acid transporter Lat2 (Slc7a8)8 in the mouse brain, raising the possibility that combinations of transporters extend control over additional developmental functions. Auditory development is highly sensitive to thyroid hormone9. Hearing loss is associated with endemic iodine defciency10, resistance to thyroid hormone11 and congenital hypothyroidism12,13. In rodents, the cochlear sen- sory epithelium, which contains the mechanosensory hair cells, is a major site of T3 action14–16. Te Trb thyroid hormone receptor gene promotes developmental remodeling of the sensory epithelium prior to the onset of 1Department of Biological Sciences, Minnesota State University Mankato, Mankato, Minnesota, 56001, USA. 2Laboratory of Endocrinology and Receptor Biology, NIDDK, National Institutes of Health, Bethesda, Maryland, 20892, USA. 3Center for Integrative Human Physiology (ZIHP) and NCCR Kidney. CH, Institute of Physiology, University of Zürich, Zürich, 8057, Switzerland. 4Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands. 5National Institute on Deafness and other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892, USA. 6Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany. David S. Sharlin and Lily Ng contributed equally to this work. Correspondence and requests for materials should be addressed to D.S.S. (email: [email protected]) or D.F. (email: [email protected]) SCIENTIFIC REPORTS | (2018) 8:4403 | DOI:10.1038/s41598-018-22553-w 1 www.nature.com/scientificreports/ Figure 1. Auditory defects in mice lacking Slc16a2 and Slc16a10. (A) Mean thresholds for the auditory- evoked brainstem response (ABR) for click and pure tone stimuli. Groups of single and double (dko) knockout mice (n = 7 to 14) at 6–12 weeks of age. Comparison of mutants to wt used a one-way ANOVA followed by Bonferroni’s t-test; ***p < 0.0001 dko versus wt at each frequency. (B) Representative ABR waveforms for a click stimulus at diferent intensities showing lack of peaks in the dko. Tresholds underlined. Note diferent response scales (μV) for each genotype. (C) Mean amplitudes of responses to a click applied at equivalent high intensity (90 dB SPL) to each genotype. Amplitudes represent the frst peak to following trough of waveforms. Groups of 3 wt and 4 to 6 mutants. Comparison of mutants to wt used a one-way ANOVA followed by Bonferroni’s t-test; ***p < 0.0001 for each genotype. (D) Distortion product otoacoustic emission (DPOAE) for adult mice. Groups of 7 mice. Te dko was impaired compared to wt (Student’s t-test) for F2 frequencies above 10.5 kHz; ns, noise background. *p = 0.0299; **p = 0.0022; ***p < 0.001. (E) Endocochlear potential in 5 wt and 6 dko mice at 3 months of age. Tree dko mice gave no detectable response. Student’s t-test, ***p < 0.001. hearing17–19. Tyroid hormone also infuences hair cell survival, and cochlear functions including the endococh- lear potential19,20 as well as the maintenance of hearing21. Te compartmentalized anatomy of the cochlea led us to hypothesize that membrane transporters are neces- sary to convey blood-borne hormone to its target tissues22. Blood enters the cochlea through the spiral modiolar artery then branches through radiating arterioles to capillary networks in the lateral wall before draining through collecting venules and the spiral modiolar vein23. Tese vessels bypass the sensory epithelium, implying a need for mechanisms that transport T3 and T4 internally. A need for transport is further implied by the requirement in auditory development for type 2 deiodinase, which amplifes levels of T3 by conversion from T422. Type 2 deiodinase is expressed in the medial cochlea and lateral wall in proximity to blood vessels but distant from the sensory epithelium24. We previously reported expression of Slc16a2 and a related thyroid hormone transporter Slc16a10 (Mct10)25 in cochlear tissues26. Here we report deafness and loss of hair cells in mice lacking Slc16a2 and Slc16a10. Treatment with T3 partly rescued phenotypes, supporting a critical role for transmembrane transport of T3 for the development and maintenance of the cochlea. Results Auditory defcits in mice lacking Slc16a2 and Slc16a10. To investigate the requirement for Slc16a2 and Slc16a10 for hearing, we analyzed the auditory-evoked brainstem response (ABR). In Slc16a2- or Slc16a10- defcient mice, auditory thresholds were similar to those in wt mice at 6–12 weeks of age (approximately young adult ages). However, in double knockout (dko) mice lacking both transporters, thresholds were markedly ele- vated compared to wt mice (Fig. 1A), thus unmasking a critical combined role for these transporters for auditory function. Responses in dko mice were defective for a click (broad band of frequencies) or pure tone stimuli at frequencies of 8, 16 and 32 kHz that span the sensitive range of hearing in mice. Defects persisted in older dko mice (6–9 months old), indicating a permanent loss of hearing. Severe impairment was also evident in weanling dko mice (3–4 weeks old), indicating an early-onset of hearing loss (not shown). Analysis of ABR waveforms showed that compared to wt mice, the residual responses that could be detected in dko mice were much diminished in magnitude (Fig. 1B). When subjected to a click stimulus at equivalent high intensity (90 dB sound pressure level), the mean amplitude of the frst peak was severely reduced by ~90% in dko compared to wt mice (Fig. 1C). In ~50% of dko mice, no specifc waveform could be detected for a click stimulus. Amplitudes were also reduced in Slc16a2 and Slc16a10 single mutants, suggesting that although thresholds were in the normal range, the magnitude of the response was subtly compromised in the absence of either transporter alone (Fig. 1C). SCIENTIFIC REPORTS | (2018) 8:4403 | DOI:10.1038/s41598-018-22553-w 2 www.nature.com/scientificreports/ Figure 2. Serum T4 and T3 levels. T4 and T3 were measured at postnatal and adult (20 week) ages (mean ± sem). Comparison across all genotypes was determined using two-way ANOVA and Tukey’s post hoc analysis. For mutants versus wt, for T4 at P12: ***p < 0.001, **p = 0.0011; at P14–16: *p = 0.0277, ***P < 0.001; at P21: ***p < 0.001, **p = 0.0059; at 20 weeks: *p = 0.0416. For T3 at P14-16: ***p < 0.001; at P21: **p = 0.0013, ***p < 0.001; at 20 weeks: ***p < 0.001, **p = 0.0051. In addition to defects in the ABR, an overall measure of auditory function, dko mice also displayed impair- ment of the distortion product otoacoustic emission (DPOAE) (Fig. 1D), a measure of the function of cochlear outer hair cells during the response to sound. Furthermore, the endocochlear potential (EP), the positive poten- tial diference in the endolymph in the scala media that is considered necessary for auditory transduction, was substantially reduced in adult dko mice compared to wt mice (Fig. 1E). Tese results indicate that cochlear defects contribute to hearing loss in dko mice. T4 and T3 levels in dko mice. We investigated levels of circulating thyroid hormone in dko mice as it is known that overt defciency of thyroid hormone at early postnatal stages causes hearing loss in mice27. At P6, during the period of cochlear remodeling before hearing normally begins, serum levels of T4 and T3 were not signifcantly diferent in dko compared to wt groups (Fig.
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